DESCRIPTION, OVERALL (provided by applicant): Islet cell transplantation represents a logical approach to a curative treatment for type 1 diabetes mellitus. However, even if the obstacles associated with transplantation, such as immunosuppression, are overcome in the future, the supply of islets remains a major problem. Clearly, novel strategies are critically needed to provide sufficient islet material for all potential patients. Embryonic stem cells (ES) offer a promising source for in vitro generation of beta cells, but before this will become reality, several challenges should be surmounted. One major issue is the limited knowledge of the developmental processes that govern patterning, growth, and differentiation in the developing embryo. The central theme of this Program is to investigate the biology of pancreatic progenitor cells. We will generate novel mouse strains and use these to investigate how pancreatic progenitor cells (PPC) are specified and how the formation of endocrine progenitor cells (EPC) is regulated? Additionally, we will investigate the mesenchymal signals that control the proliferation and endocrine lineage commitment of the PPC as well as the signals that direct the proliferation and differentiation of the EPC. We will investigate the mechanisms by which Ngn3 induce generic endocrine- and endocrine subtype-specific differentiation events as well as the mechanisms by which genes such as Nkx6.1, Arx, and Pax4 regulate endocrine subtype specification. Lastly, we will test whether the mechanisms used in the embryo for regulation of endocrine development are also utilized for beta cell formation in adults after partial pancreatic duct ligation, or whether beta cells under these circumstances are formed purely by replication of pre-existing beta cells. To accomplish our objectives we are building on previously established collaborations between the different investigators and we are expanding these to include the generation of novel tools that will be shared across project boundaries, with other BCBC investigators, and with the community at large. In particular, in this proposal we will generate several novel mouse lines and use these to investigate the cellular and molecular mechanisms that regulate beta cell development.